Environmental exposures, coupled with genetic variation, are known to have an effect on disease susceptibility. Dissecting their respective contributions remains one of the principal challenges in understanding complex diseases. Individuals with different genotypes (DNA sequence changes) may respond differently to environmental variation and generate an array of phenotypic landscapes (variations in the appearance of a trait such as a disease, or response to a drug or environmental toxicant). Such gene-by-environment (GxE) interactions are central to the theme of these GEITP pages and may be responsible for a large fraction of the unexplained variance in heritability and disease risk. Yet, disease risk –– owing to either environmental exposures and/or their interactions with genotype, remains poorly understood.

Canada’s precision medicine initiative, the Canadian Partnership for Tomorrow Project (CPTP; http://www.partnershipfortomorrow.ca) is a cohort comprising more than 315,000 Canadians, and captures over 700 variables –– ranging from longitudinal health information to environmental exposures –– to determine genetic and environmental factors contributing to chronic disease. The program includes the Quebec regional cohort, CARTaGENE, which has enrolled over 40,000, predominantly French-Canadian (FC) individuals between 40 and 70 years of age. Drawing from this founding population of individuals with largely French ancestry, authors [see attached report] selected 1,007 individuals to determine mechanisms by which genomes, the environment, and their interactions –– contribute to phenotypic variation.

They found a substantial impact of the environment on the transcriptome (the RNA transcribed from the DNA genome of each person) and clinical endophenotypes, overpowering that of genetic ancestry (The concept “endophenotype” was coined in a 1966 paper attempting to explain the geographic distribution of grasshoppers; it is a genetic epidemiological term which is used to separate behavioral symptoms into more stable phenotypes with a clear genetic connection). Air pollution was found to impact gene expression and pathways –– affecting cardio-metabolic and respiratory traits, when controlling for genetic ancestry. Lastly, authors capture four expression quantitative trait loci (eQTLs) that interact with the environment (air pollution). These findings demonstrate how the local environment can directly affect disease risk phenotypes. These data also show that genetic variation, including less common variants, can modulate an individual’s response to environmental challenges.